Maltooligosaccharide porter. The 3-D structure has been reported by Oldham et al. (2007). An altering access mechanism has been suggested for the maltose transporter resulting from rigid-body rotations (Khare et al., 2009). Bordignon et al. (2010) and Schneider et al. (2012) have reviewed the extensive knowledge available on MalEFGK2, its mode of action and its regulatory interactions. The transporter sequesters the MalT transcriptional activator at the cytoplasmic surface of the membrane in the absence of the transport substrate (Richet et al. 2012). The crystal structures of the transporter complex MBP-MalFGK2 bound with
large malto-oligosaccharide in two different conformational states have also been determined. In
the pretranslocation structure, Oldham et al. 2013 found that the transmembrane subunit
MalG forms two hydrogen bonds with malto-oligosaccharide at the reducing
end. In the outward-facing conformation, the transmrembrane subunit MalF
binds three glucosyl units from the nonreducing end. These
structural features explain why large modified malto-oligosaccharides are not
transported by MalFGK2 despite their high binding affinity to MBP. In the transport cycle, substrate is channeled from MBP
into the transmembrane pathway with a polarity such that both MBP and
MalFGK2 contribute to the overall substrate selectivity of the system (Oldham et al. 2013). Stabilization of the semi-open
MalK2 conformation by maltose-bound MBP is key to the coupling of maltose transport to ATP
hydrolysis in vivo, because it facilitates the progression of the MalK dimer from the open to the
semi-open conformation, from which it can proceed to hydrolyze ATP (Alvarez et al. 2015). Both the binding of MalE to the periplasmic side of the transmembrane complex and binding of ATP to MalK2 are necessary to facilitate the conformational change from the inward-facing state to the occluded state, in which MalK2 is completely dimerized (Hsu et al. 2017).

Alginate (MW 27,000 Da) (and Alginate oligosaccharides) uptake porter. Sphingomonas species A1 is a 'pit-forming' bacterium that directly incorporates alginate into its cytoplasm through a pit-dependent transport system, termed a 'superchannel' (Murata et al., 2008). The pit is a novel organ acquired through the fluidity and reconstitution of cell surface molecules, and through cooperation with the transport machinery in the cells. It confers upon bacterial cells a more efficient way to secure and assimilate macromolecules (Murata et al., 2008). The substrate-transport characteristics and quaternary structure of AlgM1M2SS with AlgQ1 have been determined (Maruyama et al. 2015). The addition
of poly- or oligoalginate enhanced the ATPase activity of reconstituted AlgM1M2SS coupled with one
of the periplasmic solute-binding proteins, AlgQ1 or AlgQ2. External fluorescence-labeled
oligoalginates were specifically imported into AlgM1M2SS-containing proteoliposomes in the presence
of AlgQ2, ATP, and Mg2+. The crystal structure of AlgQ2-bound AlgM1M2SS adopts an inward-facing
conformation. The interaction between AlgQ2 and AlgM1M2SS induces the formation of an alginate-binding tunnel-like structure accessible to solvent. The translocation route inside the
transmembrane domains contains charged residues suitable for the import of acidic saccharides (Maruyama et al. 2015).

The arabinosaccharide transporter AraNPQMsmX. Transports α-1,5-arabinooligosaccharides, at least up to four L-arabinosyl units; the key transporter for α-1,5-arabinotriose and α-1,5-arabinotetraose, but not for α-1,5-arabinobiose which is transported by AraE. MsmX is also used by the MdxEFG-MsmX system (3.A.1.1.36) (Ferreira and Sá-Nogueira, 2010). Involved in the uptake of pectin oligosaccharides with either MsmX or YurJ as the ATPase (Ferreira et al. 2017).

α-glucoside uptake permease, Agl3E/Agl3F/Agl3G. Plays a role in normal morphogenesis and antibiotic production. Strongly induced by trehalose and melibiose, and weakly induced by lactose and glycerol but not glucose (Hillerich and Westpheling 2006).The operon is controlled by a GntR homologue, Agl3R, and downstream of the gntR gene is a gene encoding an extracellular carbohydrase.

Maltose transporter, MusEFGKI. All five genes have been reported to be essential for uptake activity (Henrich et al. 2013). The MusI gene product is of 215 aas with 5 TMSs and comprises the founding member of a distinct family of poorly characterized protein in TC family 9.B.28.

Probable glycerophosphocholine (GPC) uptake porter (Chandravanshi et al. 2016). The system may include a receptor and three membrane proteins (of 378 aas and 6 TMSs, 299 aas and 7 TMSs, and 113 aas and 3 TMSs (?). The ATPase has not been identified.

Maltose - maltoheptose transporter, MalEFGK . MalEF is a R-M fusion protein with the MalE domain N-terminal and the MalF domain C-terminal. The protein, of 733 aas, has 8 TMSs, one N-terminal to MalE (a signal sequence for export of the MalE domain to the periplasm), an extra TMS at the N-terminus to bring the N-terminus to the periplasmic side of the inner membrane, and then the usual 6 TMSs observed for most ABC membrane proteins. MalG (M, 272 aas, 6 TMSs) and MalK (C, 374 aas) are of normal size and composition. While MalE of E. coli was able to additionally increase ATPase activity of MalFGK2Bb in vitro, the isolated MalE domain of B. bacteriovorus failed to stimulate the E. coli system (Licht et al. 2018).

Sugar (sucrose, maltose, glucose, fructose, esculin (coumarin β-glucoside)) uptake system possibly consisting of 5 or 6 proteins (see below) (Nieves-Morión and Flores 2017). These proteins are all implicated in sugar uptake, but they may include components of multiple transporters.

Oligosaccharide transporter RafEFGK. RafE, the binding protein, has be extensively characterized. It binds α-(1,6)-linked glucosides and galactosides of varying size,
linkage, and monosaccharide composition with preference for the
trisaccharides raffinose and panose. This preference is reflected in the α-(1,6)-galactoside uptake
profile of the bacterium. Structures of RafE (BlG16BP) in complex with
raffinose and panose revealed the basis for the ligand
binding plasticity, which recognizes the non-reducing
α-(1,6)-diglycosidic linkages in its ligands (Ejby et al. 2016). RafK has not be identified experimentally, but it may be NCIB protein acc# WP_022543180.1, ATP binding protein, annotated as UgpC, and this protein has been enterred into TCDB as RafK. Sugar binding substrates of RafE include: raffinose (highest affinity), panose, melibiose, stachyose, verbascose, isomaltose, isomaltotriose, isomaltotetraose, isomaltopentaose, isomaltohexaose, and isomaltoheptaose (Ejby et al. 2016).

Ribose porter. RbsA has two ATPase domains fused together; RbsB is the substrate receptor; RbsC has 10 TMSs with N- and C-termini in the cytoplasm and forms a dimer (Stewart and Hermodson, 2003). ABC importers can be divided into two classes. Type I importers follow an alternating access mechanism driven by the presence of the substrate. Type II importers accept substrates in a
nucleotide-free state, with hydrolysis driving an inward-facing conformation. RbsABC2 seems to share functional traits with both type I and type II importers, as
well as possessing unique features, and employs a distinct mechanism relative to other ABC
transporters (Clifton et al. 2014).

D-allose porter. The structure of AlsB has been solved at 1.8 Å resolution (Chaudhuri et al. 1999). Ten residues from both the domains form 14 hydrogen bonds with the sugar. 6-Deoxy-allose, 3-deoxy-glucose and ribose bind
with reduced affinity so AlbP can
function as a low affinity transporter for D-ribose (Chaudhuri et al. 1999).

The (deoxy)ribonucleoside permease; probably takes up all deoxy- and ribonucleosides (cytidine, uridine, adenosine and toxic analogues, fluorocytidine and fluorouridine tested), but not ribose or nucleobases (Webb and Hosie, 2006)

ABC sugar transporter, FruEFGK, important for the probiotic effect of Bifidobacterium longum and involved in producing acetate (Fukuda et al. 2012). The system is specific for fructose (highest affinity) ribose and xylose. All three sugars induce the system (Wei et al. 2012).

High affinity fructose uptake porter, FrtABC, Km (fructose) = ~100μM; expression of the frtABC operon is regulated by the product of the upstream gene, frtR, FrtR, a LacI/GalR-type repressor that allows activation in the presence of fructose (Ungerer et al. 2008). When FruR is eliminated, the cells become hypersensitive to fructose, and the level of fruABC expression is much higher than in the presence of wild type cells grown on fructose (Ungerer et al. 2008).

3-component ABC-type putative general nucleoside uptake porter consisting of a receptor, a putative lipoprotein with two N- and C-terminal TMSs (R; 405 aas), an integral membrane protein of about 20 TMSs in a 1 + 4 (tight) + 4 (loose) +2 +1 + 4 (tight) +4 (loose) TMS arrangement (M; 864 aas), and a cytoplasmic ATPase (C; 563 aas). It appears that the membrane protein contains a 9 (or 10) TMS repeat unit, and that there are two extra TMSs separating the two repeat units. These are homologous to the two membrane constituents of TC# 3.A.1.2.17.

Three component ABC L-glutamine porter. The basal ATPase activity (ATP hydrolysis in the absence of substrate) is mainly caused by the docking of the closed-unliganded state of GlnH onto the transporter domain of GlnPQ. Unlike glutamine, arginine binds both GlnH domains, but does not trigger their closing. Comparison of the ATPase activity in nanodiscs with glutamine transport in proteoliposomes suggested that the stoichiometry of ATP per substrate is close to two (Lycklama A Nijeholt et al. 2018).

Acidic amino acid uptake porter, AatJMQP (Singh and Röhm, 2008). It is the sole system that transports glutamate and glutamine, but it can also transport aspartate and asparagine (Singh and Röhm 2008).

Glutamine transporter, GlnQP. Takes up glutamine, asparagine and glutamate which compete for each other for binding both substrate and the transmembrane protein constituent of the system (Fulyani et al. 2015). Tandem substrate binding domains (SBDs) differ in substrate specificity and affinity, allowing cells to efficiently accumulate
different amino acids via a single ABC transporter. Analysis revealed the roles of individual residues in determining the substrate
affinity (Fulyani et al. 2013).

Basic amino acid uptake porter, ArtIQ2N2. Transports Arginine, lysine and histidine. Several 3-d structures have been solved (4YMS, 4YMT, 4YMU, etc., Yu et al. 2015). These revealed one binding site for substrate per ArtQ monomer. Heuveling et al. 2018 then showed that in the close homologue, ArtMP of Geobacillus stearothermophilus, that just one of these two sites needed to bind substrate to get transport.

Putative ABC amino acid uptake porter with 3 constituents. The membrane protein is different from other members of this subfamily in having 10 TMSs in a 3 + 2 + 3 + 2 TMS arrangement with a probable 5 TMS duplication), and the receptor has two TMSs at the N- and C-termini.

General L- (and D-)amino acid uptake porter (transports acidic, basic, polar, semipolar and hydrophobic amino acids). The amino and carboxyl groups do not need to be α since γ-aminobutyric acid (GABA) is a substrate. The system may function with additional binding proteins since L-alanine uptake is not dependent on BraC.

The phenylpropeneoid uptake porter, CouPSTW. The purple photosynthetic bacterium Rhodopseudomonas palustris is able
to grow photoheterotrophically under anaerobic conditions on a range of
phenylpropeneoid lignin monomers, including coumarate, ferulate, caffeate, and cinnamate.
RPA1789 (CouP) is the periplasmic binding-protein component of the ABC uptake system (CouPSTU). CouP binds a range of
phenylpropeneoid ligands with K d values in the nanomolar range. The
crystal structure of CouP with ferulate as the bound ligand shows H-bond
interactions between the 4-OH group of the aromatic ring with His309
and Gln305. H-bonds are also made between the carboxyl group on the
ferulate side chain and Arg197, Ser222, and Thr102 (Salmon et al. 2013).

ABC-type uptake porter for pyruvate and monocarboxylate 2-oxo acids. Pyruvate uptake has been measured and is inhibited by monocarboxylate 2-oxo-acids such as 2-oxobutyrate, 2-oxovalerate, 2-oxoisovalerate, 2-oxoisocaproate and 2-oxo 3-methylvalerate which are probably substrates (Pernil et al. 2010).

Oligopeptide porter (also takes up amino glycoside antibiotics such as kanamycin, streptomycin and neomycin as well as cell wall-derived peptides such as murein tripeptide). It transports substrate peptides of 2-5 amino acids with highest affinity for tripeptides. Also transports δ-aminolevulinic acid (ALA). [May be regulated by PTS Enzyme INtr-aspartokinase.] ATP-binding to OppDF may result in donation of peptide to OppBC and simultaneous release of OppA (Doeven et al., 2008).

Peptide transporter encoded adjacent to the putative transport system with TC#3.A.1.5.35 (Akanuma et al. 2011). Induced by exogenous S-adenosylmethionine (SAM) at a concentration of 2muM which also enhanced antibiotic production and inhibited morphological development (Park et al. 2005). SAM can be imported into cells. Mutants in the bldK genes confer resistance to the toxic tripeptide, bialaphos (Nodwell et al. 1996).

Oligopeptide transporter, OppABCDF/MppA/YgiS. MppA is a murein peptide receptor, and YgiS is a bile acid (e.g., cholate, deoxycholate) receptor that may use the Opp system for uptake. YgiS mRNA is degraded by the toxin MgsR which is regulated by the antitoxin, MgsA and this loss of the mRNA protects the cell against bile acid stress (Kwan et al. 2015).

Peptide transporter, SapABCDF. Mutants are more sensitive than the wild type to wheat alpha-thionin and to snakin-1, which is the most abundant antimicrobial peptide from potato tubers. They were also less virulent than was the
wild-type strain in potato tubers: lesion areas were 37% that of the
control, and the growth rate was two orders of magnitude lower. Thus, the interaction of antimicrobial peptides from the host with the sapA-F operon from the pathogen plays a similar role in animal and in plant bacterial pathogenesis (López-Solanilla et al. 1998).

Uncharacterized 5 component peptide uptake transporter with a receptor, two transmembrane proteins and two ATPases, as is common for this family of ABC porters. The five genes encoding this system, from metagenomic data for an uncultured Lokiarchaeon, occur adjacent to each other in the genome (Zaremba-Niedzwiedzka et al. 2017).

Putative oligopeptide transporter, OppA1A2BCDF. The two membrane proteins (OppB and OppC, of 564 and 670 aas with 13 and 15 TMSs, respectively (M-subunits)) and the two ATPases (C-subunits of 342 and 369 aas, respectively) map together, but the 4 potential receptors (R) map elsewhere on the chromosome. Two of them appear to be complete and have 734 and 738 aas, respectively, each with 2 TMSs, one N-terminal and one C-terminal. There are two other potential receptors that may not have complete sequences. They are OLS21443 (721 aas with only 1 C-terminal TMS) and OLS22122 (353 aas with only 1 N-terminal TMS).

Phosphate porter, PhoSPstABC. Serves as both a transporter and a sensor for transcriptional activation of the pho regulon in the presence of low external phosphate. The unphosphorylated EIIANtr protein of the PTS (TC# 4.A) activates PhoR, the senor kinase that phosphorylates the response regulator, PhoB, that activates the pho regulon (Lüttmann et al. 2012).

Uptake system for glycine-betaine (high affinity) and proline (low affinity) (OpuAA-OpuABC) or BusAA-ABC of Lactococcus lactis). BusAA, the ATPase subunit, has a C-terminal tandem cystathionine β-synthase (CBS) domain which is the cytoplasmic K+ sensor for osmotic stress (osmotic strength)while the BusABC subunit has the membrane and receptor domains fused to each other (Biemans-Oldehinkel et al., 2006; Mahmood et al., 2006; Gul et al. 2012). An N-terminal amphipathic α-helix of OpuA is necessary for high activity but is not critical for biogenesis or the ionic regulation of transport (Gul et al., 2012).

A proline/glycine betaine uptake system. Also reported to be a bile exclusion system that exports oxgall and other bile compounds, BilEA/EB or OpuBA/BB (required for normal virulence) (R.D. Sleator et al., 2005).

Vitamin B12 porter. The 3-D structure of BtuCDF has been solved to 2.6 Å (Hvorup et al., 2007). The conformational transition pathways of BtuCD has been revealed by targeted molecular dynamics simulations (Weng et al., 2012). Asymmetric states of BtuCD are not discriminated by its cognate substrate binding protein BtuF (Korkhov et al., 2012). ATP hydrolysis occurs at the nucleotide-binding domain
(NBD) dimer interface, whereas substrate translocation takes place at the
translocation pathway between the TM subunits, which is more than 30 angstroms away
from the NBD dimer interface. Hydrolysis of ATP appears to facilitate substrate translocation by opening the
cytoplasmic end of translocation pathway (Pan et al. 2016). The molecular mechanism of ATP hydrolysis by BtuCD-F may proceeds in a stepwise manner (Prieß et al. 2018). First, nucleophilic attack of an activated lytic water molecule at the ATP gamma-phosphate yields ADP + HPO42-. A conserved glutamate located close to the gamma-phosphate transiently accepts a proton acting as a catalytic base. In the second step, the proton transfers back from the catalytic base to the gamma-phosphate, yielding ADP + H2PO4-. These two reaction steps are followed by rearrangements of the hydrogen bond network and the coordination of the Mg2+ ion. The overall free energy change of the reaction is close to zero, suggesting that ATP binding is essential for tight dimerization of the nucleotide-binding domains and the transition of the transmembrane domains from inward- to outward-facing. ATP hydrolysis resets the conformational cycle (Prieß et al. 2018).

Iron (Fe3+)-hydroxamate porter (transports Fe3+-ferrichrome and Fe3+-ferrioxamine B with FhuD1, and these compounds plus aerobactin and coprogen with FhuD2). FhuB may function with FhuG (A6QEV8) together with FhuD2 to form a ferrichrome transporter where FhuB and FhuG have conserved arginine residues (R71 and R61, respectively) that form essential salt bridges with FhuD2 (Vinés et al. 2013).

Heme-iron (hemin) utilization transporter BhuTUV ( Brickman et al., 2006; Vanderpool and Armstrong, 2004). The crystal structures of BhuUV with or without the periplasmic
haem-binding protein BhuT have been solved (Naoe et al. 2016). The TMSs
show an inward-facing conformation, in which the cytoplasmic gate of the haem translocation pathway
is completely open. Since this conformation is found in both the haem- and nucleotide-free form, the
structure of BhuUV-T provides the post-translocation state and the missing piece in the transport
cycle of type II importers.

The putative ferric iron-desferrioxamine E uptake porter, DesEFGH. The DesE binding receptor has been characterized (Barona-Gómez et al. 2006). The remaining three (desFGH) genes cluster together without a gene encoding a receptor (R). They are believed to function with DesE based on sequence similarity and phylogenetic analyses (Getsin et al., 2013).

Metal ion (probably iron) uptake permease , YtgABC-RD. The third gene in the ytg operon is fused, the N-terminal membrane domain being fused to the C-terminal transcriptional regulator homologous to the diphtheria toxin repressor, DtxR. These two domains may be proteolitically processed yielding the two active proteins (Thompson et al. 2012).

The ZnuA18/ZnuA08/ZnuB/ZnuC zinc (Zn2+) uptake system (Hudek et al. 2013). ZnuB (M) and ZnuC (C) can function with either of two zinc ion receptors, ZnuA18 (R) which is encoded in the znuACB operon, and ZnuA08 (R) which is encoded elsewhere on the chromosome. ZnuA18 is more efficient that ZnuA08 in promoting uptake (Hudek et al. 2013).

ABC high affinity Zinc (Zn2+) uptake porter, ZnuABC. The similar system from Y. pestis has been characterized (Bobrov et al. 2014; Neupane et al. 2018). ZnuA (R) of that systems can bind up to 5 zinc ions with high affinity.

The putative cobalamin precursor/cobalt (CPC) transporter family includes proteins of about 190 aas with 4-6 TMSs. These proteins are encoded in operons that are subject to regulation by vitamin B12 (Rodionov et al. 2003). These and other ECF ABC families (3.A.1.18, 23, 25, 26, 28, 31 and 32) have been reviewed (Rempel et al. 2018).

The putative sulfate/thiosulfate transporter, YnjBCD. YnjB has 12 TMSs. The three genes encoding this system are adjacent to one encoding a thiosulfate:sulfur transferase or a rhodanese (B7L6N1). Also considered to be a thiamine transporter (Moussatova et al. 2008).

Probable 4 component ABC transporter with two ATPase of 387 and 368 aas, respectively, both annotated as MalK, one membrane protein that maps together with the two ATPases and is annotated CysW, and one receptor that maps separately for the other three and is designated MalE. It is not established that this repector maps with the other three constituents, but this has been inferred by the similarities of the two ATPases to MalK.

Putative glycerol phosphodiester uptake transporter. The three genes encoding this system are in an operon with a
gene encoding a glycerophosphodiester phosphodiesterase, providing the
evidence that this transporter might function to take up such substrates.

The NikM2 (230 aas; 5 TMSs)/NikN2 (110 aas; 2 TMSs) pair is part or all of a nickel transporter. The crystal structure of NikM2 is known (PDB 4M5C; 4M58). It possesses an additional TMS at its N-terminal region not present on other ECF transporter of known structure, resulting in
an extracellular N-terminus. The highly conserved N-terminal loop
inserts into the center of NikM2 and occludes a region corresponding
to the substrate-binding sites of the vitamin-specific S component. Nickel binds to NikM2 by coordination to four nitrogen atoms in Met1, His2 and His67. These nitrogens form a square-planar geometry, similar to that of the metal ion-binding sites in the amino-terminal Cu2+- and Ni2+-binding (ATCUN) motif (Yu et al. 2013). Constituents other than NikN2 and NikM2 are not known but may be required for activity (T. Eitinger, personal communication).

The L- and D-methionine porter (also transports formyl-L-methionine and other methionine derivatives) (Zhang et al., 2003). The 3.7A structure of MetNI has been solved. An allosteric regulatory mechanism operates at the level of transport activity, so increased intracellular levels of the transported ligand stabilize an inward-facing, ATPase-inactive state of MetNI to inhibit further ligand translocation into the cell (Kadaba et al., 2008). The structure of an MetQ homologue in Neisseria meningitidis has been solved at 2.25 Å resolution revealing a bound methionine in the cleft between the two domains (Yang et al. 2009). Conformational changes in MetQ provide substrate access through the binding protein to the transmembrane translocation pathway. MetQ likely mediates uptake of methionine derivatives through two mechanisms: in the methionine-bound form, substrate is delivered from the periplasm to the transporter (the canonical mechanism) and in the apo form, it facilitates ligand binding when complexed to the transporter (the noncanonical mechanism). This dual role of substrate-binding proteins was proposed to provide a kinetic strategy for ABC transporters to transport both high- and low-affinity substrates present in a physiological concentration range (Nguyen et al. 2018).

Putative peptide transporter, PepABC. The three components of this system are encoded in an operon with a gene encoding a peptidase (Q04MS7), providing the only tentative evidence for the substrate transported. However the similarity with the methionine transporter of Streptococcus mutans (TC# 3.A.1.24.3) suggests that this porter may also be a methionine uptake porter.

Biotin/Riboflavin ECF transport system, EcfAA'T/RibU/BioY (Karpowich and Wang 2013). RibU binds riboflavin with high affinity, and the protein-substrate complex is
exceptionally stable in solution. The crystal structure of riboflavin-bound RibU reveals an
electronegative binding pocket at the extracellular surface in which the substrate is completely
buried (Karpowich et al. 2016).

An ECF ABC transporter with 4 subunits, EcfS/EcfT/EcfA/EcfA'. EcfS is also called RibU; EcfT is also called CbiQ, EcfA is also called Cbi01, and EcfA' is also called Cbi02. This system can take up riboflavin and possibly other vitamins (Karpowich et al. 2015). ATP binding to the EcfAA' ATPases drives a conformational change that
dissociates the S subunit from the EcfAA'T ECF module. Upon release from
the ECF module, the RibU S subunit then binds the riboflavin transport
substrate. S subunits for distinct substrates compete
for the ATP-bound state of the ECF module (Karpowich et al. 2015). RibU appears to be capable of exporting riboflavin, FMN and FAD (Light et al. 2018).

The chloroplast lipid (trigalactosyl diacyl glycerol (TDG)) transporter, Tdg1,2,3 (Lu et al., 2007). Lipids such as mono- and digalactolipids are synthesized in the endoplasmic reticulum (ER) of plant cells and transferred to the thylakoid membranes of chloroplasts. Mutations in an outer chloroplastic envelope protein with 350 aas and 7 putative TMSs in the last 250 residues may catalyze translocation as part of a lipid transfer complex (Xu et al., 2003; Roston et al. 2012).

The cholesterol uptake porter (Mohn et al., 2008). Takes up cholesterol, 5-α-cholestanol,
5-α-cholestanone, β-sitosterol, etc. (It is not established that all of
these proteins comprise the system or that other gene products are not
involved.)

The putative methionine precursor/uptake transporter, MtsTUV (T is most similar to 3.A.1.23.2; U is most similar to 2.A.36.7.1 and 3.A.1.14.2; V is most similar to 3.A.1.23.2 and 3.A.1.25.1) (Rodionov et al., 2009)

RLI1 ATPase of 608 aas and 0 TMSs, ABCE. Binds to the ribosome, IF3, IF5 and IF2 to promote preinitiation complex assembly (Dong et al. 2004). ABCE proteins
are present in eukaryotes and archaea and are encoded by a single
gene in most genomes, or by two genes in a few cases. Functional
analysis of ABCE genes, primarily in Saccharomyces cerevisiae, has shown that ABCE proteins have essential functions as part of the translational
apparatus. Navarro-Quiles et al. 2018 summarized ABCE protein functions in ribosome biogenesis and recycling, with a
particular focus on their known and proposed developmental roles in
different species. The ABCE proteins might represent another class of factors contributing to the role of the ribosome in gene expression regulation.

The putative cobalamin precursor uptake transporter, CbrTUV (Rodionov et al., 2009) (CbrT is most similar to 2.A.1.15.1; CbrU is most similar to 3.A.1.26.1 (MFS; e-4); CbrV is most similar to 2.A.53.11.1 and 3.A.1.2.2 (score of 0.035)) (CbrT has 6 putative TMSs; CbrV has 8-10 putative TMSs).

The putative methylthio adenosine uptake transporter (Rodionov et al., 2009). MtaTUV (MtaT and MtaU are most similar to 3.A.1.26.1 (ThiW); MtaV is most similar to 3.A.1.25.1 (BioN) and 3.A.1.23.2 (CbiQ)).

Two component lipopolysaccharide exporter, Wzm/Wzt. Wzm is the membrane component (265 aas with 6 TMSs) which forms a ring-like large ion conductance channel. The ATPase, Wzt, functions both as the energizer and regulator (Mohammad et al. 2016).

ABC O-antigen lipopolysaccharide/polysaccharide export transporter, Wzm/Wzt of 253
aas and 6 TMSs (Wzm; also called AbcT3) and 396 aas and 0 TMSs (Wzt). The crystal
structure is available (PDB 6AN7) (Bi et al. 2018) for the Wzm-Wzt homologue from Aquifex aeolicus in an open conformation. The transporter forms a transmembrane channel that is sufficiently wide to accommodate a linear polysaccharide. Its nucleotide-binding domain and a periplasmic extension form 'gate helices' at the cytosolic and periplasmic membrane interfaces that probably serve as substrate entry and exit points (Bi et al. 2018).

Teichoic acid exporter, TagGH. Appears to be present in a large complex with the teichoic acid precursor synthetic enzymes (Formstone et al. 2008). The substrate may be the diphospholipid-linked disaccharide portion of the teichoic acid precursor (Schirner et al. 2011). 3-d structural studies have been reported (Ko et al. 2016). TagG and TagH are localized on the cytoplasmic membrane in a patch, and the TMS of TagH is important for normal transport activity (Yamada et al. 2018).

The teichoic acid precursor exporter, TarGH. May be specific for the diphospholipid linked disaccharide portion of the teichoic acid precursor (Schirner et al. 2011). TarG is the target of a small antimicrobial inhibitor of S. aureus growth (Swoboda et al. 2009). TarGH is a WTA transporter and has been purified and reconstituted in proteoliposomes (Matano et al. 2017). They showed that a new compound series inhibits TarH-catalyzed ATP hydrolysis even though the binding site maps to TarG, near the opposite side of the membrane. These are the first ABC transporter inhibitors to block ATPase activity by binding to the transmembrane domain.

ABC-2 transporter. The two genes encoding this system are adjacent to one encoding an squalene-hopene cyclase that coverts squalene to hopene. The substrate could therefore be hopene or a hydrocarbon triterpene derivative of it (Racolta et al. 2012).

ABC-2 transporter probably specific for a lantibiotic. The genes for this system are adjacent to an S2P-M50 peptidase (G0Q3D2), probably involved in pro-lantibiotic processing, as well as a lantibiotic biosynthetic enzyme (G0Q3D1) and a lantibiotic dehydratase (G0Q3D0).

Putative ABC export system (MDR?), RbbA/YhhJ/YhiI (All three genes are in a single operon; this system may comprise a single ABC exporter with MFP; substrate unknown (Moussatova et al. 2008 and unpublished observations).

Putative 5 component ABC exporter with two membrane constituents, two cytoplasmic ATPases, and one membrane fusion protein (truncated at the N-terminus, probably because of an incorrect initiation codon assignment).

Phospholipid, LPS, lipid A and drug exporter, MsbA, which flips the substrate from the inner leaflet of the cytoplasmic membrane to the outer leaflet (Eckford and Sharom, 2010). MsbA also confers drug resistance to azidopine, daunomycin, vinblastine, Hoechst 33342 and ethidium (Reuter et al., 2003). Four x-ray structures, trapped in different conformations, two with and two without nucleotide, have been solved (Ward et al., 2007). They suggest an alternating accessibility mode of transport with major conformational changes. The mechanism and conformational transitions have been discussed (Moradi and Tajkhorshid 2013). MsbA is energized both by ATP hydrolysis and the H+ electrochemical gradient (Singh et al. 2016). Mi et al. 2017 used single-particle cryo-electron microscopy to elucidate the structures of lipid-nanodisc-embedded MsbA in three functional states. The 4.2 Å-resolution structure of the transmembrane domains of nucleotide-free MsbA revealed that LPS binds deeply inside MsbA at the height of the periplasmic leaflet. Two sub-nanometre-resolution structures of MsbA with ADP-vanadate and ADP revealed a closed and an inward-facing conformation, respectively. A 2.9 A resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealed an unanticipated mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains (Ho et al. 2018). Coupled ATPase-adenylate kinase activity in ABC transporters including MsbA has been demonstrated (Kaur et al. 2016).

HlyA/MsbA family transporter of 595 aas. The gene for this protein is adjacent to and probably in the same operon as that encoding 3.A.1.106.12. They both have 6 TMSs, so they may together comprise a single heterodimeric system.

HlyA/MsbA family transporter of 577 aas. The gene encoding this protein is adjacent to and in the same operon with that encoding 3.A.1.106.11. They both have 6 TMSs, so they may together comprise a single heterodimeric system.

Lipid flippase, PglK or WlaB, of 564 aas and 6 N-terminal TMSs with a C-terminal ATPase domain. Mediates the ATP-dependent translocation of an undecaprenylpyrophosphate-linked heptasaccharide intermediate
across the cell membrane, an essential step during the N-linked
protein glycosylation pathway. Transport across the membrane is effected
via ATP-driven conformation changes. Most likely, only the polar and
charged part of the glycolipid enter the substrate-binding cavity, and
the lipid tail remains exposed to the membrane lipids during the
transmembrane flipping process (Alaimo et al. 2006; Kelly et al. 2006; Perez et al. 2015).

Peptide and multidrug resistance porter of the ABC superfamily, TmrAB. TmrA (Q72J05; 600 aas with 6 N-terminal TMSs) and TmrB (Q72J04; 578 aas with 6 N-terminal TMSs) comprise this heterodimeric transporter, both proteins of the M-C structure. The system has been found to export the dye, hoechst 33342, and to be inhibited by verapamil (Zutz et al. 2011). The subnanometre-resolution structure of detergent-solubilized TmrAB in a nucleotide-free, inward-facing conformation by single-particle
electron cryomicroscopy has been solved (Kim et al. 2015). A cavity in the
transmembrane domain is accessible laterally from the cytoplasmic side
of the membrane as well as from the cytoplasm, indicating that the
transporter lies in an inward-facing open conformation. The two
nucleotide-binding domains remain in contact via their carboxy-terminal
helices. Comparison between this structure and those of other ABC transporters suggests a possible trajectory of
conformational changes that involves a sliding and rotating motion
between the two nucleotide-binding domains during the transition from
the inward-facing to outward-facing conformations (Kim et al. 2015). A subset of annular lipids is normally invariant in composition, with negatively charged lipids binding tightly to TmrAB, suggesting that this exporter may be involved in glycolipid translocation (Bechara et al. 2015). Coupled ATPase-adenylate kinase activity in ABC transporters including TmrAB has been demonstrated (Kaur et al. 2016). A 2.7-Å X-ray structure of TmrAB has been determined. It not only shares structural homology with the antigen
translocation complex TAP, but is also able to restore antigen
processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates
several thousandfold, using only one single active ATP-binding site. It
adopts an asymmetric inward-facing state, and the
C-terminal helices, arranged in a zipper-like fashion, play a
role in guiding the conformational changes associated with substrate
transport (Nöll et al. 2017). Conformational coupling and trans-inhibition have been characterized (Barth et al. 2018).

ABC exporter. It has been suggested that it might be a glycolate exporter (Braakman et al. 2017). However it's closest hit in TCDB (31% identity in the transmembrane domain) has TC# 3.A.1.106.18, which is probably a peptide/multidrug (and possibly glycolipid) exporter with broad substrate specificity.

The biofilm inducible ABC drug (tobramycin, gentamycin, and ciprofloxacin) resistance pump, PA1875-PA1877 (Zhang and Mah, 2008). It is specifically induced and is most active when growing in a biofilm.

Probable 2646 aa extracellular adhesin (acc# C6BWI7) ABC exporter of 715 aas. Functions as a type I protein secretion system together with an MFP and an OMF which all are encoded within a single operon together with the adhesin and SiiAB homologues as for TC# 3.A.1.109.5.

Thermostable lipase, TliA (Q9ZG91; 476 aas with a C-terminal region that shows similarity to members of the RTX toxin family (1.C.11)) exporter, TliDEF. The wild type transporter has a temperature sensitive defect which can be corrected by a single mutation in TliD (Eom et al. 2016).

Nukacin ISK-1 bacteriocin exporter, NukT of 694 aas and 6 TMSs. The protease domain is N-terminal, the membrane domain is central, and the ATPase domain in C-terminal. NukT and its peptidase-inactive mutant have been expressed, purified, and reconstituted into liposomes for analysis of their peptidase and ATPase activities. The ATPase activity of the NBD (C) region is required for the cysteine-type peptidase activity, and leader peptide cleavage enhances the ATPase activity (Zheng et al. 2017).

Glycolipid exporter (under nitrogen control in heterocysts), DevABC-HgdD (Moslavac et al., 2007). Heterocyst envelope glycolipids (HGLs) function as an O2 diffusion barrier, being deposited over the heterocyst outer membrane, surrounded by an outermost heterocyst polysaccharide envelope. DevBCA and TolC form an ATP-driven efflux pump required for the export of HGLs across the Gram-negative cell wall (Staron et al., 2011). DevB, the MFP, must be hexameric to create a functional export complex. This system is under NtcA and nitrogen control and is required for heterocyst development (Fiedler et al. 2001).

Hop resistance protein, HorA. Reconstitution in phosphatidyl ethanolamine bilayers resulted in normal activity, but reconstitution in phosphatidyl choline resulted in uncoupling of ATP hydrolysis from transport and a change in the orientations of the TMSs (Gustot et al. 2010).

The cyclic peptide antibiotic, microcin J25 (MccJ25; the precursor peptide is JcjA) exporter, the self immunity protein, McjD. TolC is also required for export; Vincent and Morero, 2009. The 3-d structure has been determined to 2.7Å resolution in an outward occluded state (Choudhury et al. 2014). Binding and efflux as well as stimulation of the ATPase activity upon binding of MccJ25 have been demonstrated (Choudhury et al. 2014). This is one of two MCCJ25 exporters, the other being YojI (TC# 3.A.1.113.3). The
large conformational changes in some crystal structures may not be necessary even for a large
substrate like MccJ25 (Gu et al. 2015).

Putative coelichelin (hydroxamate siderophore) exporter, Sco0493; the gene is in a gene cluster encoding the recognized coelichelin uptake system (TC# 3.A.1.14.12) as well as coelichelin biosynthetic enzymes (Barona-Gómez et al. 2006). Sco0493 may function together with Sco0540 which is another putative ABC exporter of similar equence (see TC# 3.A.1.119.5). However, alternatively, these two genes may encode two distinct transport systems.

Putative coelichelin (hydroxamate siderophore) exporter, Sco0493; the
gene is in a gene cluster encoding the recognized coelichelin uptake
system (TC# 3.A.1.14.12) as well as coelichelin biosynthetic enzymes (Barona-Gómez et al. 2006).
Sco0493 (see TC# 3.A.1.119.4) may function together with Sco0540, both of which are putative
ABC exporters of similar sequence. Alternatively, these two genes may encode two distinct transport
systems.

ABC transporter, SgvT2 (ATP-hydrolyzing subunit of 551 aas. Functions to export griseoviridin and viridogrisein (etamycin) (Xie et al. 2017). However, it may also function as an ATP-binding cassette domain of elongation factor 3, interacting with the ribosome which stimulates its ATPase activity (Sasikumar and Kinzy 2014).

ABC protein of 558 aas and 0 TMSs, Rv2477c. It is a translation factor that gates the
progression of the 70S ribosomal initiation complex (IC, containing
tRNA (fMet) in the P site) into the translation elongation cycle by using
a mechanism sensitive to the ATP/ADP ratio. Binds to the 70S ribosome E
site where it modulates the state of the translating ribosome during
subunit translocation. It is an ABC-F subfamily protein, members of which are implicated in diverse cellular processes such as translation, antibiotic resistance, cell growth and nutrient sensing. Daniel et al. 2018 showed that Rv2477c displays strong ATPase activity (Vmax = 45 nmol/mg/min; Km = 90 muM) that is sensitive to orthovanadate. The ATPase activity was maximal in the presence of Mn2+ at pH 5.2. The protein hydrolyzed GTP, TTP and CTPas well as ATP but at lower rates. Glutamate to glutamine substitutions of amino acid residues 185 and 468 in the two Walker B motifs severely inhibited its ATPase activity. The antibiotics, tetracycline and erythromycin, which target protein translation, were able to inhibit the ATPase activity. Daniel et al. 2018 postulated that Rv2477c is involved in mycobacterial protein translation and in resistance to tetracyclines and macrolides.

MsrD of 487 aas and 0 TMSs. Involved in macrolide resistance (Zhang et al. 2016). Two ATPase domains are present in tandem. The membrane constituent is not known. However, Iannelli et al. 2018 suggested that MefA (TC# 2.a.1.21.1) can function with MsrD, and therefore that this MFS exporter can function as an ABC drug exporter. However,
the data presented seem inconsistent with this suggestion. The two genes
encoding these two proteins are adjacent to each other, suggesting that
they may somehow function together (Iannelli et al. 2018).

ATP-binding cassette subfamily F member 1, ABCF1 or ABC50, of 845 aas and 0 TMSs. There is no transmembrane protein associated with ABCF1, and this protein does not function in transport. It is required for efficient Cap- and
IRES-mediated mRNA translational initiation, not in ribosome biogenesis (Paytubi et al. 2009).

Macrolide (14- and 15- but not 16-membered lactone macrolides including erythromycin) exporter, MacAB (formerly YbjYZ). Both MacA and MacB are required for activity (Tikhonova et al., 2007). MacAB functions with TolC to export multiple drugs and heat-stable enterotoxin II (enterotoxin STII) (Yamanaka et al., 2008). The crystal structure of MacA is available (Yum et al., 2009). MacB is a dimer whose ATPase activity and macrolide-binding capacity are regulated by the membrane fusion protein MacA (Lin et al., 2009). Xu et al. (2009) have reported the crystal structure of the periplasmic region of MacB which they claim resembles the periplasmic domain of RND-type transporters such as AcrB (TC# 2.A.6.2.2). Also exports L-cysteine (Yamada et al., 2006). The periplasmic membrane proximal domain of MacA acts as a switch in stimulation of ATP hydrolysis by the MacB transporter (Modali and Zgurskaya, 2011). Fitzpatrick et al. 2017 presented an electron cryo-microscopy structure of the tripartite assembly (MacAB-TolC) at near-atomic resolution. A hexamer of the periplasmic protein MacA bridges a TolC trimer in the outer membrane to a MacB dimer in the inner membrane, generating a quaternary structure with a central channel for substrate translocation. A gating ring found in MacA may act as a one-way valve in substrate transport. The MacB structure features an atypical transmembrane domain with a closely packed dimer interface and a periplasmic opening that is the likely portal for substrate entry from the periplasm, with subsequent displacement through an allosteric transport mechanism (Fitzpatrick et al. 2017). The structure of ATP-bound MacB has been solved, revealing precise molecular details of its mechanism (Crow et al. 2017). MacB has a fold that is different from other structurally characterized ABC transporters and uses a unique molecular mechanism termed mechanotransmission. Unlike other bacterial ABC transporters, MacB does not transport substrates across the inner membrane in which it is based, but instead couples cytoplasmic ATP hydrolysis with transmembrane conformational changes that are used to perform work in the extra-cytoplasmic space. In the MacAB-TolC tripartite pump, mechanotransmission drives efflux of antibiotics and export of a protein toxin from the periplasmic space via the TolC exit duct. Homologous tripartite systems from pathogenic bacteria similarly export protein-like signaling molecules, virulence factors and siderophores (Greene et al. 2018).

ABC transporter of unknown function, but aspects of its structure and mechanism of action are known (Yuan et al. 2001; Zoghbi and Altenberg 2013).Nucleotide-binding domain dimerization occurs as a result of binding to the natural nucleotide triphosphates, ATP, GTP, CTP and UTP, as well as the analog ATP-gamma-S. All the natural nucleotide triphosphates are hydrolyzed at similar rates, whereas ATP-gamma-S is not hydrolyzed. The non-hydrolyzable ATP analog AMP-PNP, frequently assumed to produce the nucleotide-bound conformation, failed to elicit nucleotide-binding domain dimerization (Fendley et al. 2016).

MacAB-TolC MDR effllux porter. Exports macrolide antibiotics, virulence factors, peptides and cell envelope precursors. The 3-d crystal structure of MacB has been solved at 3.4 Å resolution (Okada et al. 2017). MacB forms a dimer in which each protomer contains a nucleotide-binding domain and four TMSs that protrude in the periplasm into a binding domain for interaction with the membrane fusion protein MacA. It has unique structural features (Okada et al. 2017).

ABC3-type efflux porter, YtrEF, encoded within an operon, ytrABCDEF, apparently encoding two ABC exporters, one, YtrBCD, with TC# 3.A.1.153.1, and the other, this one. The operon is induced in early stationary phase under the control of YtrA, a GntR-type HTH transcriptional regulator, probably a repressor (Yoshida et al. 2000). These authors suggest this operon may be involve in acetoin secretion and/or reutilization.

ABC transport system with a type 3 ABC membrane protein (386 aas and 4 TMSs; B9GHI1) and an ABC ATPase (234 aas; B8GHI2). The encoding genes are adjacent to those encoding a putative transport system with TC# 9.B.29.2.7.

Lipoprotein translocation system (translocates lipoproteins from the inner membrane to periplasmic chaperone, LolA, which transfers the lipoproteins to an outer membrane receptor, LolB, which anchors the lipoprotein to the outer membrane of the Gram-negative bacterial cell envelope) (see 1.B.46; Narita et al., 2003; Ito et al., 2006; Watanabe et al., 2007). The structure of ligand-bound LolCDE has been solved (Ito et al., 2006). LolC and LolE each have 4 TMSs (1+3). Unlike most ATP binding cassette transporters mediating the transmembrane flux of substrates, the LolCDE complex catalyzes the extrusion of lipoproteins anchored to the outer leaflet of the inner membrane. The LolCDE complex is unusual in that it can be purified as a liganded form, which is an intermediate of the lipoprotein release reaction (Taniguchi and Tokuda, 2008). LolCDE has been reconstituted from separated subunits (Kanamaru et al., 2007). LolE binds the outer membrane lipoprotein, PAL (Mizutani et al. 2013).

Putative ABC transporter, LolCDE, with three components, similar to (but substantially different from) LolC, LolD and LolE of E. coli. The three genes encoding these proteins are adjectent to each other on the bacteria chromosome, but there is no direct experimental evidence that they function together as lipoprotein exporters.

6TMS putative ABC transporter protein with an ABC-type ATPase encoded by the adjacent gene. This memebrane protein also maps adjacent to protein fragments that show similarity to ABC transport proteins as well as a protease (9.B.218.1.4; D4TYE3).

The 2 or 3 component bacitracin-resistance efflex pump, BcrAB or BcrABC (Podlesek et al., 1995; Bernard et al., 2003) (BcrA is most similar to SpaF (3.A.1.124.2), but BcrB (5-6 TMSs) is only distantly related to other ABC2-type membrane proteins (Wang et al., 2009). BcrC is not sufficiently similar to detect similarity in BLAST searches. BcrC (5TMSs) belongs to the PAP2 phosphatase superfamily and may not be a contituent of the BcrAB transporter. Transcription is regulated by BcrR, a one-component transmembrane signal transduction system (Darnell et al. 2019).

Putative ABC exporter with two membrane proteins of 478 and 417 aas and 6 TMSs respectively, and one ATPase. The encoding genes are adjacent to a TonB-dependent OMR with possible specificity for a siderophore. Thus, this ABC exporter could transport a siderophore.

The VraFG ABC transporter interacts with GraXSR [GraX, Q7A2W7; GraS, A6QEW9; GraR, A6QEW8] to form a five-component system required for cationic antimicrobial peptide sensing and resistance (Falord et al., 2012). VraX has been termed a two component system connector and may not be a component of the transporter.

The hetrodimeric ABC transporter, TM287/TM288. The 2.9-Å crystal structure has been solved in the inward-facing
state. The two nucleotide binding domains (NBDs) remain in contact through an interface involving
conserved motifs that connect the two ATP hydrolysis sites.
AMP-PNP binds to a degenerate catalytic site which deviates from
the consensus sequence in the same positions as the eukaryotic homologs,
CFTR (TC# 3.A.1.202.1) and TAP1-TAP2 (TC# 3.A.1.209.1) (Hohl et al. 2012). The structural basis for allosteric crosstalk (positive cooperativity) between the two ATP binding sites has been studied (Hohl et al. 2014). The two NBDs exhibit unexpected differences and flexibility (Bukowska et al. 2015). It exports daunomycin and the nonfluorescent 2,7-bis(carboxyethyl)-5(6)-carboxyfluorescein-acetoxymethylester (BCECF-AM) (Hohl et al. 2012). Timachi et al. 2017 observed
hydrolysis-independent closure of the NBD dimer, further stabilized as the consensus site
nucleotide is committed to hydrolysis.

Two component multidrug efflux pump with the 6 TMS membrane domain preceding the ATPase domain in both proteins. Confers resistance to erythromycin and tetracycline and catalyzes export of Hoechst 33342 (Moodley et al. 2014). Expression is induced by the presence of erythromycin.

The FtsX/FtsE ABC transporter (Arends et al., 2009) (FtsX is of the type III topology). FtsEX directly recruits EnvC to the septum via an interaction between EnvC and a periplasmic loop of FtsX. FtsEX variants predicted to be ATPase defective still recruit EnvC to the septum but fail to promote cell separation. Amidase activation via EnvC in the periplasm is regulated by conformational changes in the FtsEX complex mediated by ATP hydrolysis in the cytoplasm. Since FtsE has been reported to interact with FtsZ, amidase activity may be coupled with the contraction of the FtsZ cytoskeletal ring (Yang et al., 2011).

The exoprotein (including α-amylase) secretion system, EcsAB(C) (Leskelä et al., 1999). Also may play roles in sporulation, competence (Leskelä et al., 1996) and transformation using purified DNA (Takeno et al., 2011). An involvement of EcsC in transport is not established, but it is homologous to the C-terminus of the P-type ATPase, 3.A.3.31.2.

Functionally uncharacterized ABC2 transporter #1. This system is encoded by two genes that overlap and are therefore probably translationally coupled; they are in the same operon with the genes for 2.A.1.144.2.

Functionally uncharacterized ABC2 transporter #2. This system is encoded by two genes that overlap and are therefore probably translationally coupled; they are in the same operon with the genes for 2.A.1.144.1.

Functionally uncharacterized ABC2 transporter #4 of 751 aas with 18 putative TMSs. The first 6 TMSs are duplicated to give the N-terminal 12 TMSs. The last 6 TMSs are non-homologous and are of the DUF95 family (TC #9.B.98).

Putative two component ABC exporter with a membrane protein of 573 aas and 12 TMSs and an ATPase encoded adjacent to the membrane protein and also adjacent to a gene encoding an adenine glycosylase, probably within a single operon.

ABC immunity system, TrnFG, protecting the bacteria from the bacteriocin, thuricin CD. TrnF is of 213 aas and 6 TMSs while TrnG is of 285 aas and 0 TMSs. A 79 aa protein, TrnI with 2 TMSs, also provides immunity against thuricin CD, but the mechanism is unknown (Mathur et al. 2014). These proteins incoded in the thuricin operon.

Putative ABC transporter consisting of an ATPase and three membrane proteins having 4, 10 and 2 TMSs, respectively. The structure of the ATPase is similar to those of ABC transorteers, and expression is down regulated in response to cold shock (Gerwe et al. 2007).

Putative 3-compenent ABC transporter consisting of two membrane proteins and a cytoplasmic ATPase. Adjacent to genes coding for a MoaJ/NirJ iron-sulfur nitrite-like oxidoreductase and an antilisterial bacteriocin biosynthetic enzyme, AlbA (B5YBB2 and 3, respectively). The system could be a bacteriocin exporter.

LPS export system, LptF (M), LptG (M) and LptB (C). This system is also listed in TCDB under TC#1.B.42.1.2 as part of a multicomponent system. The entire system is described in detail there. LptB2FG extracts LPSs from the IM and transports them to the outer membrane. Luo et al. 2017 reported the crystal structure of nucleotide-free LptB2FG from P. aeruginosa.
It shows that LPS transport proteins LptF and LptG each contain a TM
domain (TMD), a periplasmic beta-jellyroll-like domain and a coupling
helix that interacts with LptB on the cytoplasmic side. The LptF and
LptG TMDs form a large outward-facing V-shaped cavity in the IM.
Mutational analyses suggested that LPS may enter the central cavity
laterally, via the interface of the TMD domains of LptF and LptG, and is
expelled into the beta-jellyroll-like domains upon ATP binding and
hydrolysis by LptB. These studies suggest a mechanism for LPS extraction
by LptB2FG that is distinct from those of classical ABC transporters that transport substrates across the IM (Luo et al. 2017). LptB2FG extracts LPS from the periplasmic face of the IM through a pair of lateral gates and then powers transperiplasmic transport to the OM through a slide formed by either of the periplasmic domains of LptF or LptG, LptC, LptA and the N-terminal domain of LptD. The structural and functional studies of the seven lipopolysaccharide transport proteins provide a platform to explore the unusual mechanisms of LPS extraction, transport and insertion from the inner membrane to the outer membrane (Dong et al. 2017). LptB2 binds novobiocin which stimulates its export activity and renders the membrane more impermeable to novobiocin (Luo et al. 2017 reported the crystal structure of nucleotide-free LptB2FG from P. aeruginosa.
It shows that LPS transport proteins LptF and LptG each contain a TM
domain (TMD), a periplasmic beta-jellyroll-like domain and a coupling
helix that interacts with LptB on the cytoplasmic side. The LptF and
LptG TMDs form a large outward-facing V-shaped cavity in the IM.
Mutational analyses suggested that LPS may enter the central cavity
laterally, via the interface of the TMD domains of LptF and LptG, and is
expelled into the beta-jellyroll-like domains upon ATP binding and
hydrolysis by LptB. These studies suggest a mechanism for LPS extraction
by LptB2FG that is distinct from those of classical ABC transporters that transport substrates across the IM (Luo et al. 2017). LptB2FG extracts LPS from the periplasmic face of the IM through a pair of lateral gates and then powers transperiplasmic transport to the OM through a slide formed by either of the periplasmic domains of LptF or LptG, LptC, LptA and the N-terminal domain of LptD. The structural and functional studies of the seven lipopolysaccharide transport proteins provide a platform to explore the unusual mechanisms of LPS extraction, transport and insertion from the inner membrane to the outer membrane (Dong et al. 2017). LptB2 binds novobiocin which stimulates its export activity and renders the membrane more impermeable to novobiocin (Luo et al. 2017). LptB2FG extracts LPS from the periplasmic face of the IM through a pair of lateral gates and then powers transperiplasmic transport to the OM through a slide formed by either of the periplasmic domains of LptF or LptG, LptC, LptA and the N-terminal domain of LptD. The structural and functional studies of the seven lipopolysaccharide transport proteins provide a platform to explore the unusual mechanisms of LPS extraction, transport and insertion from the inner membrane to the outer membrane (Dong et al. 2017). LptB2 binds novobiocin which stimulates its export activity and renders the membrane more impermeable to novobiocin (May et al. 2017).

Putative ABC exporter of the YjgP/Q (LptFG) family. The membrane protein has 772 aas and 12 TMSs in a (3 + 3)2 duplicated topology. The gene adjacent to this membrane protein gene encodes an ABC1 ATPase of 583 aas and 6 N-terminal TMSs with a C-terminal ATPase domain. Most ATPases of family 3.A.1.152. are of the ABC2-type.Thus, it is unlikely that this protein serves to energized the YjgP/Q-dependent transport process. This protein is in TCDB with TC# 3.A.1.106.17.

Uncharacterized ABC system of the YjgP/Q family; the two membrane proteins are encoded by adjacent genes, but the gene for the ATPase was not found. However, a soluble OstA homologue (Q5SL97) of 824 aas is encoded adjacent to the two membrane protein-encoding genes.

Lipopolysaccharide transporter that exports LPS from the external surface of the cytoplasmic membrane to the outer membrane, LptB2FG. The 134-kDa protein complex is unique among ABC transporters because it extracts lipopolysaccharide from the external leaflet of the inner membrane and propels it along a filament that extends across the periplasm to directly deliver lipopolysaccharide into the external leaflet of the outer membrane. Dong et al. 2017 reported the crystal structure of this transporter in which both LptF and LptG are composed of a beta-jellyroll-like periplasmic domain and six TMSs. LptF and LptG together form a central cavity containing highly conserved hydrophobic residues. Structural and functional studies suggest that LptB2FG uses an alternating lateral access mechanism to extract lipopolysaccharide and traffic it along the hydrophobic cavity toward the transporter's periplasmic domains. The structure has been presented by Dong et al. 2017.

ABC transporter complex YtrBCD that may play a role in acetoin utilization during stationary phase and sporulation (Yoshida et al. 2000). Expression is induced early in the stationary phase. The six ytr genes form a single operon, transcribed from a promoter present upstream of ytrA. YtrA, which
possesses a helix-turn-helix motif of the GntR family, may be a
repressor that regulates its own transcription as well as the whole operon. Inactivation of the
operon led to a decrease in the maximal cell yield and less-efficient
sporulation. B. subtilis produces acetoin as
an external carbon storage compound and then reuses it later during
stationary phase and sporulation. Possibly the Ytr porter plays a role (Yoshida et al. 2000). The YtrEF system, believed to be a distinct ABC efflux system (M. Saier, unpublished results), can be found under TC# 3.A.1.122.19.

The phage infection protein of 901 aas, PIP (Geller et al. 1993). The PIP family (3.A.1.155) includes large proteins with 1 N-terminal hydrophobic
TMS, a hydrophilic domain of variable length, and 5 C-terminal putative
TMSs. The functionally characterized protein from Lactococcus lactis is of 901 aas (Geller et al., 1993). Homologues obtained with one PSI-BLAST iteration include members of the MmpL family of the RND superfamily (e.g., a Bacillus protein, gi#89208076; 1038 aas). With poorer scores, a protein
annotated as an ABC-2-like sequence (gi#89200681; 392 aas with 1 TMS
followed by a 150 residue hydrophilic domain followed by a C-terminal 5
putative TMSs) was retrieved. Another protein annotated as ABC-2 was
smaller with 6 putative TMSs in a 2 + 3 + 1 arrangement (gi#57234453;
241 aas). The hydrophilic domain in these proteins may show sequence similarity with the large periplasmic hydrophilic domains of RND porters (2.A.6.1 - 9).

P-glycoprotein-1 MDR exporter. Transports multiple drugs, cancer chemotherapy agents, cancer unrelated compounds and many xenobiotics including ivermectin (Ardelli 2013). The crystal structure at 3.4 A resolution is available (Jin et al. 2012). It has 4,000x higher affinity for actinomycin D in the membrane bilayers than in detergent. A "ball and socket joint" and salt bridges similar to ABC importers suggested that both types of systems, importers and exporters, use the same mechanism to interconnect ATP hydrolysis with transport and achieve alternating access of the substrate binding site to the two sides of the membrane.

Mitochondrial ABCB10 transporter. Essential for erythropoiesis, and for protection of mitochondria
against oxidative stress. The 3-d structures of several conformations are available (3ZDQ; Shintre et al. 2013).

12 TMS multidrug resistance transprter of 1318 aas, AbcB15 (Xiong et al. 2010) is the probable exporter of dichlorodiphenyltrichloroethane (DDT). Expression is induced by treatment with DDT, and this transporter appears to be responsible for DDT tolerance by pumping it out of the cell (Ning et al. 2014).

Half sized ABCB1 drug (verapamil; rhodamine 6G) exporter of specificity similar to that of P-glycoprotein (3.A.1.201.1). The 3-d structures of the unbound (2.6 Å) and the allosteric inhibitor-bound (2.4 Å) forms have been determined (Kodan et al. 2014). The outward opening motion is required for ATP hydrolysis. Kodan et al. 2019 have reported a pair of structures of this homodimeric P-glycoprotein: an outward-facing conformational state with bound nucleotide, and an inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å, respectively. Features that can be clearly visualized include ATP binding with octahedral coordination of Mg2+; an inner chamber that significantly changes in volume with the aid of tight connections among TMSs 1, 3, and 6; a glutamate-arginine interaction that stabilizes the outward-facing conformation; and extensive interactions between TMS1 and TMS3, a property that distinguishes multidrug transporters from floppases (Kodan et al. 2019).

Multidrug exporter, MDR49 or Pgp of 1302 aas and 12 TMSs. Exports many drugs as well as pollutants such as polycyclic aromatic hydrocarbons (PAHs) which are major sources of air, water and soil pollution. MDR49 is expressed at all developmental stages of the life cycle and in many tissues (Vache et al. 2007).

ABC multidrug exporter, MDR1 of 1341 aas, 12 TMSs and two ATPase domains in an MCMC arrangement. Miltefosine (hexadecylphosphocholine), the first orally available drug available to treat leishmaniasis, is pumped out of the parasite by MDR1, a P-glycoprotein-like transporter. Overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites and resistance (Pérez-Victoria et al. 2006).

Multidrug resistance exporter of 1331 aas and 12 TMSs, TratrD or MDR2. Almost identical throughout must of its length to F2PRR1 from T equinum of 1235 aas and 12 TMSs (Martins et al. 2016). Displays increased levels of transcription of the TruMDR2 gene when mycelia were exposed to acriflavine, benomyl, ethidium bromide, ketoconazole, chloramphenicol, griseofulvin, fluconazole, imazalil, itraconazole, methotrexate, 4-nitroquinoline N-oxide (4NQO) or tioconazole. Disruption of the TruMDR2 gene rendered the mutant more sensitive to terbinafine, 4NQO and ethidium bromide than the control strain, suggesting that this transporter plays a role in modulating drug susceptibility in T. rubrum (Fachin et al. 2006).

P-glycoprotein, Pgp, ABCB1, of 1241 aas and 12 TMSs with a domain order MCMC. Exports geraniol and other monoterpenes. Demissie et al. 2018 reported two structures of this homodimeric P-glycoprotein: an
outward-facing conformational state with bound nucleotide and an
inward-facing apo state, at resolutions of 1.9 Å and 3.0 Å,
respectively. Features that could be clearly visualized include ATP binding with octahedral coordination of Mg2+;
an inner chamber that significantly changes in volume with the aid of
tight connections among transmembrane helices (TMSs) 1, 3, and 6; a
glutamate-arginine interaction that stabilizes the outward-facing
conformation; and extensive interactions between TMS1 and TMS3, a property
that distinguishes multidrug transporters from floppases. These
structural elements were proposed to participate in the mechanism of the
transporter (Demissie et al. 2018).

CFTR of Epithelial ion channel that plays a role in the regulation of epithelial ion and water transport
and fluid homeostasis (Bagnat et al. 2010; Navis et al. 2013; Navis and Bagnat 2015). It mediates the transport of chloride ions across the cell membrane. Channel activity is coupled to ATP hydrolysis. The ion
channel is also permeable to HCO3-; selectivity depends on
the extracellular chloride concentration. CFTR exerts its function in part by
modulating the activity of other ion channels and transporters, and it contributes to the regulation of the pH and the ion content of the
epithelial fluid layer. Required for normal fluid
homeostasis in the gut (Bagnat et al. 2010) and for normal volume expansion of Kupffer's vesicle during
embryonic development as well as for normal establishment of left-right body
patterning (Navis et al. 2013; Roxo-Rosa et al. 2015). It is also required for normal resistance to infection by Pseudomonas aeruginosa (Phennicie et al. 2010).

ABCD4, PMP70-related, P70R, PMP69 or PXMP1L of 606 aas. Forms homo- and heterodimers. May be involved in intracellular processing of vitamin B12 (cobalamin), possibly by playing a role in the lysosomal release of vitamin B12 into the
cytoplasm. Defects cause Methylmalonic aciduria and homocystinuria type cblJ (MAHCJ), a disorder of cobalamin metabolism characterized by decreased levels of
the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) (Coelho et al. 2012). The amino treminal region determines the subcellular localization of this and other ABC
subfamily D proteins (Kashiwayama et al. 2009).

ABC transporter, BclA, of 586 aas and 6 TMSs in a 2 + 2 + 2 arrangement in the N-terminus and the ABC domain in the C-terminus. It is a peptide transprter required for bacteroid differentiation. It catalyzes import of peptides called nodule-specific cysteine-rich (NCR) peptides in the
symbiotic nodule cells which house the bacteroids. NCR peptides are
related to antimicrobial peptides of innate immunity, but they induce the
endosymbionts into a differentiated, enlarged, and polyploid state (Guefrachi et al. 2015). BclA is required for the formation of differentiated and functional
bacteroids in the nodules of the NCR peptide-producing Aeschynomene legumes. BclA catalyzes import of NCR peptides
and provides protection against the antimicrobial activity of these
peptides. Moreover, BclA can complement the role of the related BacA transporter of Sinorhizobium meliloti, which has a similar symbiotic function in the interaction with Medicago legumes (Guefrachi et al. 2015).

Eye pigment precursor transporter, White. Part of a membrane-spanning permease system
necessary for the transport of pigment precursors into pigment cells
responsible for eye color. White dimerize with Brown for the transport
of guanine. The Scarlet (TC# 3.A.1.204.17) and White complex transports a metabolic
intermediate (such as 3-hydroxy kynurenine) from the cytoplasm into the
pigment granules (Mackenzie et al. 2000). The White and Scarlet proteins are located in the
membranes of pigment granules within pigment cells and retinula cells
of the compound eye. Somatic knockouts of white in the noctuid moth, Helicoverpa armigera block pigmentation of the
egg, first instar larva and adult eye, but germ-line knockouts of white are recessive lethal in the
embryo (Khan et al. 2017).

Drug resistance transporter, ABCG2 (MXR; ABCP) (human breast cancer resistance protein, BCRP) (Moitra et al., 2011). It exports urate and haem in haempoietic cells (Latunde-Dada et al., 2006) as well as cytotoxic agents (mitoxantrone, flavopiridol, methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, topotecan, and resveratrol), fluorescent dyes (Hoechst 33342) and other toxic substances (PhIP and pheophorbide a) (Özvegy-Laczka et al., 2005). It also transports folate and sterols: estradiol, and probably cholesterol, progesterone, testosterone and tamoxifen (Janvilisri et al., 2003; Breedveld et al., 2007). It is a homotetramer (Xu et al., 2004). It forms a homodimer bound via a disulfide bond at Cys-603 which stabilizes the protein against ubiquitin-mediated degradation in proteosomes (Wakabayashi et al., 2007), and can for dodecamers with 12 subunits (Xu et al. 2007). It has 6 established TMSs with the N- and C- termini inside (Wang et al., 2008). The following drugs are exported from human breast cancer cell line MCF-7: miloxantrone, daunorubicin, doxorubicin and rhodamine123). Also transports reduced folates and mono-, di- and tri-glutamate derivatives of folic acid and methotrexate (Assaraf et al., 2006). It is an active glutathione efflux pump (Brechbuhl et al., 2010). Mutations in ABCG2 cause hyperuricemia and gout , which led to the identification of urate as a physiological subsrate for ABCG2; it catalyzes elimination of urate across the renal tubular apical membrane (Prestin et al. 2014). Zafirlukast antagonizes ABCG2 multidrug resistance (Sun et al., 2012). Inhibited by Sildenafil (Shi et al., 2011) and lapatinib derivatives (Sodani et al., 2012). Mutation of basic residues can increase or decrease drug efflux activities (Cai et al. 2010). A substrate of ABCG2 is d-luciferin, allowing bioluminescent immaging of drug efflux across the blood-brain barrier. Inhibitors include Ko143, gefetinib and nilotinib (Bakhsheshian et al. 2013). Fluorescent substrates have been identified (Strouse et al. 2013). Telabinib reverses chemotheraputic MDR mediated by ABCG2 (Sodani et al. 2014). Residues involved in protein trafficking and drug transport activity have been identified (Haider et al. 2015). The 3-d structure in the inward facing conformation has been solved (Rosenberg et al. 2015). Durmus et al. 2015 and Westover and Li 2015 have reviewed BCRP-mediated transport of cancer chemotheraputic agents. A role for the C2-sequence of the ABCG2
linker region in ATP binding and/or hydrolysis coupled to drug efflux has been proposed (Macalou et al. 2015). Functions at the blood:placenta barrier of the mouse (Kumar et al. 2016). The Q141K variant exhibits
decreased functional expression and thus increased drug accumulation and decreased urate secretion, and the R482 position, which plays
a role the substrate specificity, is located in one of the substrate binding
pockets (László et al. 2016). Naturally occurring single nucleotide polymorphisms in humans giving rise to amino acyl residue substitutions in the transmembrane domains result in impared transport of Lucifer Yellow and estrone sulfate (Sjöstedt et al. 2017). A cryoEM structure revealed two cholesterol molecules bound in the multidrug-binding pocket that is located in a central, hydrophobic, inward-facing translocation pathway between TMSs. A multidrug recognition and transport mechanism was proposed, and disease-causing single nucleotide polymorphisms were rationalized. The structural basis of cholesterol recognition by G-subfamily ABC transporters was also revealed (Taylor et al. 2017). Catalyzes efflux of ochratoxin A (OTA) (Qi et al. 2017). Penylheteroaryl-phenylamide scaffold allows ABCG2 inhibition. 4-Methoxy-N-(2-(2-(6-methoxypyridin-3-yl)-2H-tetrazol-5-yl)phenyl)benzamide (43) exhibited a highest potency (IC50=61nM)), selectivity, low intrinsic toxicity, and it reversed the ABCG2-mediated drug resistance at 0.1muM (Köhler et al. 2018). ABCG2 acts in concert with ABCA1, ABCB1 and ABCG4 to efflux amyloid-β
peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). Inhibited by dacomitinib (Fan et al. 2018). A specific inhibitor, CCTA-1523, is a potent, selective and reversible modulator of ABCG2 (Patel et al. 2017). Exports uric acid (urate), and its loss promotes onset of hyperuricemia. It has potential as a regulator of Gout (Fujita and Ichida 2018). High resolution cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar have been solved (Jackson et al. 2018). Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid-exposed surface of the TMSs (Jackson et al. 2018). Multiple drug binding pockets and residues involved in binding have been identified (Cox et al. 2018). The third transmembrane helix and adjacent regions of ABCG2 may interact with AT1 receptor antagonists, giving rise to drug-drug interactions in multi-drug regimens (Ripperger et al. 2018). The system is inhibitied by hetero aryl phenyl inhititors (Köhler et al. 2018). It is present in the blood-brain, blood-testis and maternal-fetal barriers, and cryoEM of a mutant shows the protein in a substrate-bound pre-translocation state and an ATP-bound post-translocation state (Manolaridis et al. 2018). A single molecule of estrone-3-sulfate (E1S) is bound in a central, hydrophobic, cytoplasm-facing cavity about halfway across the membrane. Only one molecule of E1S can bind in the observed binding mode. In the ATP-bound state, the substrate-binding cavity has collapsed while an external cavity has opened to the extracellular side of the membrane. The ATP-induced conformational changes include rigid-body shifts of the transmembrane domains, pivoting of the nucleotide-binding domains (NBDs), and a change in the relative orientation of the NBD subdomains (Manolaridis et al. 2018). This shows how the energy of ATP binding extrudes E1S and other substrates, and suggests that the size and binding affinity of compounds are important for distinguishing substrates from inhibitors. Its structure, mechanism and inhibitory propensity have been reviewed (Kapoor et al. 2018). Y6, an Epigallocatechin Gallate Derivative, Reverses ABCG2-Mediated Mitoxantrone Resistance (Zhao et al. 2018).

The ABCG5 (sterolin-1)/ABCG8 (sterolin-2) heterodimeric neutral sterol (cholesterol and plant sterols) (e.g., sitosterol) (phosphoryl donors ATP > CTP > GTP > UTP) exporter; present in the apical membranes of enterocytes and hepatocytes. Cholesteryl oleate, phosphatidyl choline and enantiomeric cholesterol are poorly transported (mutation of either ABCG5 or ABCG8 cause sitosterolemia and coronary atherosclerosis) (Zhang et al., 2006; Wang et al., 2006; 2011). Involved in cell signalling, creation of membrane asymmetry and apoptosis (Quazi and Molday, 2011). The ABCG5/ABCG8 heterodimer (G5G8) mediates excretion of neutral sterols in liver and
intestines. Mutations disrupting G5G8 cause sitosterolaemia, a disorder characterized by sterol
accumulation and premature atherosclerosis. Lee et al. 2016 used crystallization in lipid bilayers to
determine the X-ray structure in a nucleotide-free state at 3.9 A resolution. The structure reveals a new
transmembrane fold that is present in a large and functionally diverse superfamily of ABC
transporters. The transmembrane domains are coupled to the nucleotide-binding sites by networks of
interactions that differ between the active and inactive ATPases, reflecting the catalytic asymmetry
of the transporter (Lee et al. 2016). High expression levels of both ABCG5 and ABCG8 were observed in liver, the digestive tract and the mammary gland. The system plays roles in lipid and sterol intestinal absorption, biliary excretion, and lipid trafficking and excretion during lactation (Viturro et al. 2006).

The epidermal plasma membrane cuticular lipid (wax) exporters, ABCG11/ABCG11 and ABCG11/ABCG12;
ABCG11 is also called Wbc11; Desperado (DSO); COF1; PEL1. ABCG12 is also called CER5, WBC12 and D3 (Panikashvili and Aharoni 2008). Required for the cuticle and pollen coat development by controlling
cutin and possibly wax transport to the extracellular matrix. Involved in
developmental plasticity and stress responses (Bird et al. 2007). ABCG11 can traffic to the plasma membrane in the absence of ABCG12 and can form flexible dimers. By contrast, ABCG12 was retained in the endoplasmic reticulum in the absence of ABCG11, indicating that ABCG12 can only form dimers with ABCG11 in the plasm membrane of epidermal cells. Some ABCG proteins may be promiscuous, having multiple partnerships,
while others may form obligate heterodimers for specialized
functions (McFarlane et al. 2010).

The intracellular sterol transporter, ABCG1 (Tarling and Edwards, 2011). Involved in cell signalling, creation of membrane asymmetry and apoptosis (Quazi and Molday, 2011). Promotes cholesterol efflux from macrophages to the mature forms of HDL (HDL2 and HDL3) (Voloshyna and Reiss, 2011). Plays a role in arteriosclerosis (Münch et al. 2012). The diverse functions invarious cell types have been reviewed by Tarling (2013). Many mammals have two isoforms, long and short, but mice have only the short isoform (Burns et al. 2013). Residues have been identified that play roles in stability, oligomerization and trafficking (Wang et al. 2013). Both the full-length and the short isoforms of ABCG1
can dimerize with ABCG4 (3.A.1.204.20) (Hegyi and Homolya 2016). Cholesterol-binding motifs in the membrane may allow transport of different cholesterol pools (Dergunov et al. 2018).

Scarlet. Part of a membrane-spanning permease system necessary for the transport
of pigment precursors into pigment cells responsible for eye color. The scarlet and white (TC# 3.A.1.204.1) complex probably transports a metabolic intermediate (such as
3-hydroxy kynurenine) from the cytoplasm into the pigment granules (Tearle et al. 1989). These proteins are located in the
membranes of pigment granules within pigment cells and retinula cells
of the compound eye (Mackenzie et al. 2000). Knockouts of scarlet in the noctuid moth, Helicoverpa armigera, are viable and produce pigmentless first instar larvae and yellow adult
eyes lacking xanthommatin (Khan et al. 2017).

Brown. Part of a membrane-spanning permease system necessary for the transport
of pigment precursors into pigment cells responsible for eye color.
Brown and white (TC# 3.A.1.204.1) dimerize for the transport of guanine (Campbell and Nash 2001). Knockouts of brown in the noctuid moth, Helicoverpa armigera, show no phenotypic effects on viability or
pigmentation (Khan et al. 2017).

ATP-binding cassette sub-family G member 4, ABCG4, half transporter of 646 aas. ABCG4 can form homodimers, but also
heterodimers with its closest relative, ABCG1. Both the full-length and the short isoforms of ABCG1
can dimerize with ABCG4, whereas the ABCG2 multidrug transporter is unable to form a heterodimer
with ABCG4 (Hegyi and Homolya 2016). ABCG4 is
predominantly localized to the plasma membrane. AbcG4 acts in concert with ABCA1, ABCB1 and ABCG2 to efflux amyloid-β
peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018).

ABCG25 of 662 aas and 6 TMSs in a C-M domain arrangement. Transports abscisic acid, ABA, a plant hormone that influences developmental processes, including seed and bud dormancy, the control of organ size and stomatal closure (Lefèvre and Boutry 2018).

ABCG6 of 727 aas and 6 TMSs in a CM domain arrangement. This transporter is an ABCG half-transporters that is required for synthesis of an effective suberin barrier in roots and seed coats, while ABCG2 and ABCG20 may serve the same function (Yadav et al. 2014). Seed coats of abcg2 abcg6 abcg20 triple mutant plants had increased permeability to tetrazolium
red and decreased suberin content. The root system of triple mutant
plants was more permeable to water and salts in a zone complementary to
that affected by the Casparian strip. Suberin of mutant roots and seed
coats had distorted lamellar structure and reduced proportions of
aliphatic components. Root wax from the mutant was deficient in
alkylhydroxycinnamate esters (Yadav et al. 2014).

ABC exporter, ABCG1 of 415 aas and 3 C-terminal TMSs. This sequence may be incomplete, being C-terminally truncated. The protein is necessary of microsporidal infections in the midguts of silkworms (He et al. 2018).

The multidrug resistance protein, Pdr11p, mediates sterol uptake by promoting movement of sterols from the plasma membrane to the endoplasmic reticulum where esterification occurs (Li and Prinz, 2004).

The plasma membrane Pdr10, a negative regulator for incorporation of Pdr12 (TC# 3.A.1.205.3) into detergent-resistant membranes, a novel role for members of the ABC transporter superfamily (Rockwell et al., 2009) (most like 3.A.1.205.1; 67% identity).

ABC1 transporter. Excretes secondary metabolites such as terpenes. Involved in both
constitutive and jasmonic acid-dependent induced defense. Secretes the terpenes, sclareol andsclareolide and thereby confers resistance to the fungus, B.cinerea (Stukkens et al. 2005).Induced by sclareolide and sclareol, and by some phytohormones
such as jasmonic acid (JA) and ethylene. Strongly induced by compatible
pathogens such as B. cinerea and the bacterium, Pseudomonas syringae pv
tabaci, as well as by non pathogenic bacteria such as P. fluorescens, and
P. marginalis pv marginalis (Grec et al. 2003).

AbcG34 of 1453 aas and 12 TMSs. Secretes a major phytoalexin, camalexin, which on the leaf surface protects the plant against necrotophic pathogens (Khare et al. 2017). Also protects against the antifungal agent, sclareol. AtABCG34 expression was induced by Abrassicicola inoculation as well as by methyl-jasmonate, a defense-related
phytohormone, and AtABCG34 was polarly localized at the external face of
the plasma membrane of epidermal cells of leaves and roots (Khare et al. 2017). Probably transports a variety of alkaloids v(Lefèvre and Boutry 2018).

Multidrug resistance (MDR) exporter, (Np)AbcG5/PDR5 of 1498 aas and 12 TMSs. NpABCG5/NpPDR5 is barely expressed in leaf tissues under normal
conditions, but its expression is induced by the biotic stress hormone
methyl jasmonate, or when tissues are wounded or chewed by an insect. NpABCG5/NpPDR5 confers resistance to the
herbivore Manduca sexta (Toussaint et al. 2017).

Plasma membrane ABCG1 or PDR1a of 1434 aas and 12 TMSs. 85% identical to TC# 3.A.1.205.21. PDR1 secretes plastid-produced diterpene(s) that are the antimicrobial compounds active in preinvasion defense, as well as the sesquiterpenoid, capsidiol, the major phytoalexin produced by Nicotiana and Capsicum species. Capsidiol is produced in plant tissues attacked by pathogens and plays a
major role in postinvasion defense by inhibiting pathogen growth (Shibata et al. 2016). This protein and ABCG2/PDR2, a close paralogue, export the same compounds and are essential for resistance to the potato late blight pathogen Phytophthora infestans. Thus, ABCG1/2 are involved in the export of both antimicrobial diterpene(s)
for preinvasion defense and capsidiol for postinvasion defense against
P. infestans.

ABCG30 or PDR2 of 1400 aas and 12 TMSs in a C-M-C-M domain arrangement. Responds to abiotic stresses such as heavy metals (Cd2+, Pb2+, etc), and is regulated by hormones related to pathogenic defenses (Crouzet et al. 2006) . It may be a heavy metal efflux pump, but may also transport abscisic acid, influencing developmental processes, including seed and bud dormancy, the control of organ size and stomatal closure (Lefèvre and Boutry 2018).

Multidrug (anthracycline) resistance organic anion efflux pump (ABC-C6; MRP6; MOAT-E - the ectopic mineralization disorder, pseudoxanthoma elasticum disease (PXE), protein (Vanakker et al. 2013)) exports glutathione conjugates including leukotriene C4, DNP, and N-ethylmaleimide S-glutathione; also exports anthracyclines, epipodophyllotoxins, cisplatin, and probably exports probenecid, benzbromarone and indomethacin (Chen and Tiwari, 2011). The system participates in networds of complex diseases (De Vilder et al. 2015). This transporter has an extra N-terminal domain (TMD0) and a loop, L0. TMD0 is not required for transport function, but L0 maintains ABCC6 in a
targeting-competent state for the basolateral membrane and might be involved in regulating the NBDs (Miglionico et al. 2016). PXE is a disease of altered
elastic properties in multiple tissues. Many of these mutations influence various steps in the
biosynthetic pathway, minimally altering local domain structure but adversely impacting ABCC6
assembly and trafficking (Ran and Thibodeau 2016). PXE is an ectopic, metabolic mineralization disorder that affects the skin, eye, and vessels. ABCC6 is assumed to mediate efflux of one or several small molecule compounds from the liver cytosol to the circulation. In mice, abrogating ABCC6 function causes alterations in the liver metabolic profile, suggesting that PXE is a metabolic disease originating from a liver disturbance (Rasmussen et al. 2016). Thus, MRP6 is involved in the regulation of tissue calcification in mammals, and mutations are associated with human ectopic calcification disorders. Comparative analyses of the ABCC6 and ABCC1 from invertebrates to vertebrates where a bony endoskeleton first evolved. The ABCC6 gene was only found in bony vertebrate genomes (Parreira et al. 2018).

Cyclic nucleotide (cAMP and cGMP) efflux pump, MRP8 (ABCC11); also exports other nucleoside and nucleotide analogues, and confers resistance to fluoropyrimidines and the anti-AIDS drug, 2',3'-dideoxycytidine (Guo et al., 2003). Human earwax consists of wet and dry types. Dry earwax is frequent in East Asians, whereas wet earwax is common in other populations. A SNP, 538G --> A (rs17822931), in the ABCC11 gene is responsible for determination of earwax type. Cells with allele A show a lower excretory activity for cGMP than those with allele G. The 538G --> A SNP is the first example of DNA polymorphism determining a visible genetic trait (Yoshiura et al., 2006). Binding sites in ABCC11 for cGMP (cyclic guanosine
monophosphate) and 5FdUMP (5-fluoro-2'-deoxyuridine-5'-monophosphate), the active metabolite of the
anticancer drug 5-fluoro-uracil, have been identified (Honorat et al. 2013). MRP8 generally exports a variety of anionic lipophilic compounds including antiviral and anticancer agents (Arlanov et al. 2015).

The general organic anion exporter, MRP5 (MOATC). It exports cyclic AMP, cyclic GMP, 5'-FUMP, glutathione and glutathione conjugates and antimonial tartrate). Also transports reduced folates as well as mono-, di- and tri-glutamate derivatives of folic acid and methotrexate (Assaraf et al., 2006). When overexpressed, it can lower the intracellular concentration of nucleoside/nucleotide analogs, such as the antiviral compounds PMEA (9-(2-phosphonylmethoxyethyl)adenine) or ganciclovir, and of anticancer nucleobase analogues, such as 6-mercaptopurine, after their conversion into the respective nucleotides (Ritter et al., 2005).

The possible HCO3- transporter, HLA3 (Duanmu et al., 2009). Activation of HLA3 expression in high CO2 acclimated cells, where HLA3
is not expressed, resulted in increased Ci accumulation and Ci-dependent
photosynthetic O2 evolution specifically in very low CO2 concentrations, which confirms that HLA3 is indeed involved in Ci
uptake. It also suggests that HLA3 is mainly associated with HCO3-transport in very low CO2 concentrations, conditions in which active CO2 uptake is limited (Gao et al. 2015).

The vacuolar MRP1 of 1622 aas. Also called ABCC1 and EST1. It sequesters in the vacuole glutathione conjugates, folate mono-glutamates (pteroyl-1-glutamate) and antifolates (methotrexate); (Raichaudhuri et al. 2009) (86% identical to MRP2 (3.A.1.208.5). ABCC1 and ABCC2 confer tolerance to cadmium and mercury, in addition to their role in arsenic detoxification. MRP1 of Lithospermum erythrorhizon may play a direct or indirect role in transmembrane transport of shikonin (Zhu et al. 2017). ABCC1 and ABCC2 regulate stomatal closing and open as well as anthocyanin transport (Frelet-Barrand et al. 2008).

MRP4 ABC anthocyanin/phytic acid efflux porter of 1510 aas and 12 TMSs. It exports anthocyanin in aleurone tissues (). ABC transporter that may affect phytic acid
transport and compartmentalization. It function directly or indirectly
in removing phytic acid from the cytosol. and is required for phytic acid accumulation in developing seeds. It is expressed most highly in embryos, but also in immature endosperm,
germinating seed and vegetative tissues. Silencing expression of this
transporter in an embryo-specific manner produced low-phytic-acid,
high-Pi transgenic maize seeds that germinate normally (Shi et al. 2007). Phytic acid
is the primary storage form of phosphorus in cereal grains and other
plant seeds.

Multidrug resistance pump, MRP1 or ABCC1 of 1515 aas and 17 putative TMSs. The ABCC1 gene is expressed at all larval stages and in at least nine different tissues, particularly in the fifth-instar larvae and Malpighian tubules (Chen et al. 2018). MRP1 (ABCC1) serves as a functional receptor for the insect toxins, Cry1A and Cry2Ab (Chen et al. 2018).

Multidrug resistance protein, MRP4 or ABCC4, of 1349 aas and 12 TMSs in an M-C-M-C domain order. The non-steroidal anti-inflammatory drug (NSAID) diclofenac, known to cause hyperuricemia and concomitant visceral gout in Gyps vultures may be a result of interference with renal uric acid excretion. Three species of Gyps vultures are on the verge of extinction due to nephrotoxic veterinary diclofenac having entered the food chain, and because the toxicity of different avian species to the NSAIDs like diclofenac varies. MRP4, an organic anion transporter in birds, plays a unique role in unidirectional efflux of urate into the proximal renal tubular lumen for excretion and maintenance of homeostasis. Barik et al. 2019 characterized the MRP4 channel at the molecular level to predict its structural based ligand binding properties in Gallus domesticus (Indian domestic chicken) and Gyps himalayensis (the Himalayan griffon vulture)including point and insertional mutational variants.

MHC heterodimeric peptide exporter (TAP) (from cytoplasm to the endoplasmic reticulum) (TAP1=ABCB2; TAP2=ABCB3) (defects in TAP1 or TAP2 cause immunodeficiency) (TAP1/TAP2 is stabilized by tapasin isoforms 1, 2 and 3) (Raghuraman et al., 2002). TAP1 has 10 TMSs, 4 unique N-terminal TMSs and 6 TMSs that form the translocation pore with N- and C-termini in the cytosol (Schrodt et al., 2006). The TAP2 nucleotide binding site appears to be the main catalytic active site driving transport suggesting asymmetry in the transporter (Perria et al., 2006). The TAP complex shows strict coupling between peptide binding and ATP
hydrolysis, revealing no basal ATPase activity in the absence of
peptides (Herget et al., 2009). There are three binding sites on TAP1 for tapasis which interconnects TAP and MHC class I, promotes TAP stability and facilitates heterodimerization (Leonhardt et al. 2014). TAP is the target of GN1 (TC#8.B.25.1.1), a virally encoded protein inhibitor of viral peptide exposure on the cell surface (Verweij et al. 2008; Rufer et al. 2015). Tapasin (448 aas; O15533) stabilizes TAP2 (Papadopoulos and Momburg 2007). Tapasin is involved in the association of MHC class I
with the transporter associated with antigen processing (TAP) and in the
assembly of MHC class I with peptide (peptide loading). TAP plays a key role in the adaptive immune defense against infected or malignantly transformed cells by translocating proteasomal degradation products into the lumen of the endoplasmic reticulum for loading onto MHC class I molecules. TAP transports peptides from 8 to 40 residues, including even branched or modified molecules, suggestive of structural flexibility of the substrate-binding pocket. The bound peptides in side-chains' mobility was strongly restricted at the ends of the peptide, whereas the central region was flexible. Peptides bind to TAP in an extended kinked structure, analogous to those bound to MHC class I proteins (Herget et al., 2011). TAP translocates proteasomal degradation products from the cytosol into the lumen of the endoplasmic reticulum, where these peptides are loaded onto MHC class I molecules by a macromolecular peptide-loading complex (PLC) and subsequently shuttled to the cell surface for inspection by cytotoxic T lymphocytes. As a central adapter protein, tapasin (O15533) (Li et al. 2000) recruits other components of the PLC at the N-terminal domains of TAP. Koch et al. 2006 found that the N-terminal domains of human TAP1 and TAP2 independently bind to tapasin, thus providing two separate loading platforms for PLC assembly. Tapasin binding is dependent on the first N-terminal TMS of TAP1 and TAP2, demonstrating that these two helices contribute independently to the recruitment of tapasin and associated factors (Koch et al. 2006). The endoplasmic reticulum-resident human cytomegalovirus glycoprotein US6 (gpUS6) inhibits peptide translocation by the transporter associated with antigen processing (TAP) to prevent loading of major histocompatibility complex class I molecules and antigen presentation to CD8+ T cells. gpUS6 associates with preformed TAP1/2 heterodimers (Halenius et al. 2006).

Homodimeric transporter ABCB9 or TAPL. Transports a broad spectrum of peptides (low affinity) from the cytosol to the lysosomal lumen. It exists in two forms (812 aas and 1257 aas). The latter full length protein confers resistance to taxanes and anthracyclines (Kawanobe et al., 2012). Resistance and transport were demonstrated for paclitaxel and docetaxel. Transports a broad range of peptides of 6-60aas (23aas optimal). Has also been detected in the ER. It is stabilized by interaction with LAMP-1 and LAMP-2 (see 9.A.16) (Demirel et al., 2012). The protein consists of a core transporter plus an N-terminal transmembrane domain (TMD0) required to tageting to the lysosome and for interactions with LAMP-1 and -2 (Tumulka et al. 2013). TMD0 has a four transmembrane helix topology with a short helical segment in a lysosomal loop (Bock et al. 2018).

The mitochondrial iron transporter, ATM1. The crystal structures of the nucleotide-free and glutathione-bound inward facing, open conformations have been solved at 3.1 and 3.4 Å resolution respectively (Srinivasan et al. 2014). The glutathione binding site is near the inner membrane surface in a large cavity. An unknown sulfur compound appears to be exported by Atm1 and used for the synthesis of iron/sulfur centers in the cytoplasm. This compound also signals iron sufficiency/deficiency to the nucleus (Philpott et al. 2012).

Mitochondrial ABC transporter, ATM3, involved in iron homeostasis (Chen et al. 2007) and heavy metal resistance (Kim et al. 2006). There are three isoforms: ATM1, ATM2 and ATM3 (Chen et al., 2007). ATM3 can replace the yeast iron/sulfur cluster exporter better than ATM1 or ATM2. Atm3 is most similar to the human and yeast homologues, TC# 3.A.1.210.4 and 3.A.1.210.1, 51% and 47% identical, respectively. It may function in cytosolic iron-sulfur cluster biogenesis (Bernard et al. 2009) as well as molybdenum cofactor biosynthesis (Teschner et al. 2010). It performs an essential function in the generation of cytoplasmic
iron-sulfur proteins by mediating export of Fe/S cluster precursors. Not required for
mitochondrial and plastid Fe-S enzymes. Probably involved in the export
of cyclic pyranopterin monophosphate (cPMP) from mitochondria into the
cytosol. Mediates glutathione-dependent resistance to heavy metals such
as cadmium and lead, as well as their transport from roots to leaves.
Regulates nonprotein thiols (NPSH) and the cellular level of glutathione
(GSH).

ABCB3 of 704 aas and 6 TMSs. Essential for the biosynthesis of heme in mitochondria, and of iron-sulfur centers (ISC) in the cytoplasm. The protein is an ABC half-transporter that has an N-terminal extension required to target LmABCB3 to the
mitochondrion. Martínez-García et al. 2016 showed that LmABCB3 interacts with porphyrins and is required for the
mitochondrial synthesis of heme from a host precursor. It complements the severe growth defect in yeast
lacking ATM1, an orthologue of human ABCB7, involved in exporting from mitochondria a gluthatione-containing compound required for the
generation of cytosolic ISC. Docking analyzes using trypanothione, the main thiol in the
parasite, showed how both, LmABCB3 and yeast ATM1, contain a
similar thiol-binding pocket. LmABCB3 is an essential gene as dominant negative
inhibition of LmABCB3 is lethal for the parasite. The
abrogation of only one allele of the gene did not impede promastigote
growth in axenic culture but prevented the replication of intracellular
amastigotes and the virulence of the parasites in a mouse model of
cutaneous leishmaniasis.

The retinal-specific ABC transporter (RIM protein, ABCR or ABCA4) (Stargardt's disease protein, involved in retinal/macular degeneration) in the rod outer segment. Changes in the oligomeric state of the nucleotide binding domains of ABCR are coupled to ATP hydrolysis and might represent a signal for the TMDs of ABCR to export the bound substrate (Biswas-Fiss 2006). The ABCA4 porter flips N-retinylidene-phosphatidylethanolamine, a product generated from the photobleaching of rhodopsin, from the lumen to the cytoplasmic side of disc membranes following the photobleaching of rhodopsin, insuring that retinoids do not accumulate in disc membranes (Molday, 2007; Molday et al. 2009; Tsybovsky et al. 2013). It also transports several vitamin A derivatives (Sun, 2011) and phosphatidylethanolamine in the same
direction. Mutations, known to cause Stargardt disease, decrease
N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine transport activities (Quazi et al. 2012).

cAMP-dependent and sulfonylurea-sensitive anion transporter, ABCA1 of 2261 aas. Key gatekeeper influencing and possibly catalyzing intracellular phospholipid and cholesterol transport (Orlowski et al. 2007). Interacts with the MEGF10 protein. 95% identical to the mouse orthologue, 3.A.1.211.1. Cholesterol efflux from THP-1 macrophages decreases in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression (Wang et al. 2017). The cryoEM struction (4.1 Å) revealed that the two transmembrane domains contact each other through a narrow interface in the intracellular leaflet of the membrane, and two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allowed potential interpretation of their diverse pathogenic mechanisms. Structural-based analyses suggested a plausible ""lateral access"" mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm. AbcA1 acts in concert with ABCB1, ABCG2 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). One substrate of systems ABCA1, ABCB1 and ABCC1 is arsenate, where ABCC1 is most effective while ABCA1 and ABCB1 are less effective (Zhou et al. 2018). ABCA1 transports lipids and cholesterol onto apolipoprotein E (APOE( (Castranio et al. 2018). Cholesterol binding to the ABCA1 may interfere with ATP binding in both nucleotide-binding domains of the ABCA1 structure (Dergunov et al. 2018).

ATP-binding cassette sub-family A member 6, ABCA6 of 1617 aas. Ttransporter which may play a role in macrophage lipid homeostasis. Up-regulated during monocyte differentiation into macrophages. Down-regulated by cholesterol loading of macrophages.

ATP-binding cassette sub-family A member 9, ABCA9 of 1624 aas. May play a role in monocyte differentiation and lipid homeostasis. Expressed in fetal tissues with highest expression in fetal heart and kidney. Up-regulated during monocyte differentiation into macrophages. Down-regulated by cholesterol loading of macrophages.

ATP-binding cassette sub-family A member 10, ABCA10 of 1543 aas. May play a role in macrophage lipid homeostasis. Highly expressed in skeletal muscle, heart, brain and gastrointestinal tract. Down-regulated by cholesterol loading of macrophages.

ABC protein, OptrA, of 619 aas and 0 TMSs, having the domain order of C-C. It is not involved in the export of drugs (oxazolidinones and phenicols)out of the cell and may confer ribosomal protection (Wang et al. 2018).